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At least 19 recordsLinked to original sources
PubMed2006

Collapsin response mediator protein 1 mediates reelin signaling in cortical neuronal migration.

Collapsin response mediator protein 1 (CRMP1) is one of the CRMP family members that mediates signal transduction of axon guidance molecules. Here, we show evidence that CRMP1 is involved in Reelin (Reln) signaling to regulate neuronal migration in the cerebral cortex. In crmp1-/- mice, radial migration of cortical neurons was retarded. This phenotype was not observed in the sema3A-/- and crmp1+/-;sema3A+/- cortices. However, CRMP1 was colocalized with disabled-1 (Dab1), an adaptor protein in Reln signaling. In the Reln(rl/rl) cortex, CRMP1 and Dab1 were expressed at a higher level, yet tyrosine phosphorylated at a lower level. Loss of crmp1 in a dab1 heterozygous background led to the disruption of hippocampal lamination, a Reeler-like phenotype. In addition to axon guidance, CRMP1 regulates neuronal migration by mediating Reln signaling.

Animals↗
PubMed2005

Expression of collapsin response mediator proteins 1, 2 and 5 is differentially regulated in newly generated and mature neurons of the adult olfactory system.

Collapsin-response mediator proteins (CRMPs) are highly expressed in the developing brain where they take part in several aspects of neuronal differentiation. CRMPs are still present postnatally, but their function remains speculative in the adult brain. We studied the expression and localization of CRMP1, CRMP2 and CRMP5 in two areas of the nervous system with persistent neurogenesis in adult mice, the olfactory mucosa and the olfactory bulb. In the olfactory mucosa, we have established that CRMP expression is restricted to postmitotic cells of the olfactory neurons lineage. CRMP5 is coexpressed with growth associated protein of 43 kDa (GAP43) in immature olfactory neurons and is down-regulated in olfactory marker protein-positive mature neurons. In contrast, CRMP1 and CRMP2 persist at all stages of differentiation from immature GAP43-positive to fully mature olfactory neurons. In the olfactory bulb, CRMP1, CRMP2 and CRMP5 are abundant in neuronal progenitors of the subependymal layer and in differentiating interneurons. In both areas, the subcellular distribution of CRMP1 or CRMP2 is different in mature vs. immature neurons, suggesting that these proteins are sequentially involved in various cellular events during neuronal lifetime. The variations of CRMP expression following axotomy are consistent with their differential localization and functional involvement in immature vs. mature neurons of the olfactory system. Our data bring new insight to the putative functions of CRMPs within areas of the adult nervous system with permanent neurogenesis, some related to differentiation of newly generated neurons but others occurring in mature neurons with a limited lifespan.

Amino Acid Sequence↗
PubMed2006

The collapsin response mediator protein 1 (CRMP-1) and the promyelocytic leukemia zinc finger protein (PLZF) bind to UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis.

Sialic acids (Sia) are expressed as terminal sugars in many glycoconjugates. They are involved in a variety of cell-cell interactions and therefore play an important role during development and regeneration. UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme in the de novo synthesis of Sia and it is a regulator of cell surface sialylation. Inactivation of GNE in mice results in early embryonic lethality. Mutations in the GNE gene are of clinical relevance in hereditary inclusion body myopathy, but these mutations do not necessarily decrease the enzymatic activity of GNE. In this study, we searched for novel function of the GNE protein beside its enzymatic function in the Sia biosynthesis. We here report the identification of novel GNE-interacting proteins. Using a human prey matrix we identified four proteins interacting with GNE in a yeast two-hybrid assay. For two of them, the collapsin response mediator protein 1 and the promyelocytic leukemia zinc finger protein, we could verify protein-protein interaction with GNE.

Animals↗
PubMed2004

Expression of axon guidance molecules and their related genes during development and sexual differentiation of the olfactory bulb in rats.

Axon guidance molecules and related proteins such as semaphorin 3A, neuropilin-1, plexin-1, netrin-1, growth-associated protein, olfactory marker protein, cypin and collapsin response mediator proteins guide the development of neural circuits in the olfactory bulb. In this study, transcriptions of these genes were examined in the olfactory bulb of female, male and neonatal testosterone propionate-treated female rats at the ages of 2, 5, 10, 15, 20, 25, 30 and 45 days. The semaphorin 3A, neuropilin-1, growth-associated protein and collapsin response mediator protein 1-5 genes were expressed significantly higher during the early development stages than in adulthood while the opposite is true for the olfactory marker protein. The expression profile of cypin and netrin-1 was relatively constant through development. A late effect of the neonatal testosterone propionate treatment on netrin-1, growth-associated protein, olfactory marker protein, collapsin response mediator proteins 1, 3, 4 and cypin gene expression was observed. The expression profiles of collapsin response mediator proteins and their related genes in the developing olfactory bulb confirmed most studies on the relationship between collapsin response mediator proteins and development in the brain. Sex differences of semaphorin 3A, neuropilin-1 as well as collapsin response mediator protein 3 at the early development stage and the late effect of neonatal testosterone propionate treatment on the expressions of netrin-1, growth-associated marker protein, cypin and collapsin response mediator proteins 1, 3 and 5 genes may indicate a possible role of these molecules on sexual differentiation of the olfactory bulb.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Mapping of eight testis-specific genes to mouse chromosomes.

We previously identified eight testis-specific genes using antibodies raised against testicular germ cells. They are expressed during spermatogenesis and are presumed to be involved in testicular germ cell differentiation and sperm formation. We have mapped the genomic loci for these testis-specific genes using restriction fragment length variants in interspecific backcross mice. The calmegin gene (Clgn) was mapped to Chr 8. The synaptonemal complex protein gene 1 (Sycp1) probe hybridized with two sequences on different chromosomes; Sycp1-rs2 was mapped to Chr 3, whereas Sycp1-rs3 was mapped to Chr 7. The relaxin-like factor gene (Rlnl) was mapped to Chr 8, and collapsin response mediator protein 1 (Crmp1) was mapped to Chr 5. Three novel genes encoding testis-specific proteins A2 (Tsga2), A8 (Tsga8), and A12 (Tsga12) were mapped to chromosomes 3, X, and 10, respectively.

Animals↗
PubMed2004

Haplotype and linkage disequilibrium analysis of the CRMP1 and EVC genes.

In this report, we present the haplotype and linkage disequilibrium (LD) pattern in the Collapsin Response Mediator Protein 1 (CRMP1) and Ellis-van Creveld syndrome (EVC) gene region. We genotyped eight different single nucleotide polymorphisms (SNPs) in the CRMP1 and EVC genes in 90 control individuals of diverse ethnicity. The minor allele frequencies ranged from 3.3-49.4%, with most having a frequency >25%. A total of 37 haplotypes were derived from these eight polymorphisms, with only one haplotype having a frequency >10%. Pairwise LD analysis showed a weak but significant LD between markers located about 243 kb apart in this region. The LD was significant between markers spaced about 208 kb apart in EVC, whereas no LD was found between a pair of markers located about 5 kb apart in CRMP1. However, in general, LD correlated with the distance between loci. The CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene, in which mutations also cause low frequency sensorineural hearing loss (LFSNHL). The haplotypes obtained from these polymorphisms will be useful to track the segregation of phenotypes in families with Ellis-van Creveld syndrome, Weyers acrodental dysostosis, LFSNHL and Wolfram syndrome type 1.

Base Sequence↗
PubMed2004

Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis.

BACKGROUND: Tumor invasion and metastasis cause most deaths in cancer patients. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells, but few mechanistic details are known. We investigated the roles of CTGF and collapsin response mediator protein 1 (CRMP-1) in metastasis and invasion of human lung adenocarcinoma. METHODS: We compared vector control-transfected cells with corresponding CTGF gene-transfected cells. Invasive activity was measured with a modified Boyden chamber assay, and metastatic activity was measured in an animal model. We used CTGF deletion mutants, CTGF and CRMP-1 antisense oligonucleotides, and anti-integrin and anti-CRMP-1 antibodies to investigate the functional relationship between CTGF and CRMP-1. Expression of CTGF protein in 78 lung adenocarcinoma specimens was investigated immunohistochemically. All statistical tests were two-sided. RESULTS: Invasive (both P<.001) and metastatic (P<.001 and P=.003, respectively) activities were lower in cells that overexpress CTGF than in vector control cells. Expression of CRMP-1 was higher in CTGF-transfected clones than in vector control cells, and its level decreased after cells were treated with anti-integrin alpha(v)beta3 and alpha(v)beta5 antibodies. Reduced levels of CRMP-1 protein after the transfection of CRMP-1-specific antisense oligonucleotides, but not sense oligonucleotides, increased the invasiveness of CTGF-transfected cells (mean numbers of invasive CTGF-transfected cells treated with 20 microM CRMP-1-specific sense and antisense oligonucleotides were 327 and 516 cells, respectively [difference = 189 cells, 95% confidence interval [CI] = 156 to 221 cells; P<.001]). The CT module of CTGF was the region primarily responsible for the increased expression of CRMP-1 and the inhibition of invasion (mean numbers of invasive cells expressing full-length CTGF and CT module-deleted mutant were 148 and 385 cells, respectively [difference = 237 cells, 95% CI = 208 to 266 cells; P<.001]). Reduced expression of CTGF in lung cancer specimens was statistically significantly associated with the risk of more advanced-stage disease (stages III and IV versus stages I and II; P=.001), lymph node metastasis (P =.014), and shorter survival (median survival with high levels of CTGF = 66.7 months and median survival for low levels = 18.2 months; difference = 48.5 months, 95% CI = 33.5 to 63.5 months; P =.02). CONCLUSION: CTGF inhibits metastasis and invasion of human lung adenocarcinoma by a CRMP-1-dependent mechanism.

Adenocarcinoma↗
PubMed2000

Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia.

Comparative brain proteome analysis is a new strategy to discover proteins and therefore genes whose altered expression may underlie schizophrenia. This strategy does not require an a priori theory of the pathogenesis or the mode of inheritance of schizophrenia. Using proteome analysis we previously compared the hippocampal proteome, that is, those proteins expressed by the hippocampal genome, of seven schizophrenic individuals with the hippocampal proteome of seven control individuals, matched for age and post mortem delay.1 We found 18 proteins that were significantly altered in concentration in the schizophrenic hippocampus (P < 0.05), when compared to control tissue. One of these proteins was characterised, by N-terminal sequencing, as diazepam binding inhibitor whose gene maps to 6q12-q21. Here we characterise a further three of the 18 proteins as: manganese superoxide dismutase, 6q25.3, T-complex protein 1, 6q25.3-q26 and collapsin response mediator protein 2, 8p21. That three of these four characterised proteins should map to the long arm of the same chromosome is significant (P < 0.002) and suggests the importance of chromosome 6q in schizophrenia. These results indicate that antioxidant defence is altered in the schizophrenic hippocampus and suggest that segregation distortion, of schizophrenia susceptibility genes, may be a possible causative factor in the high incidence of schizophrenia. Molecular Psychiatry (2000) 5, 85-90.

Carrier Proteins↗
PubMed2006

Potential target genes of EMX2 include Odz/Ten-M and other gene families with implications for cortical patterning.

EMX2 and PAX6 are expressed by cortical progenitors and specify area patterning. We used representational difference analysis (RDA) to compare expressed RNAs from wild type and Emx2-/- cortex and identified 41 unique clones. Using secondary screening by in situ hybridization, we selected five genes for further analysis, Cdk4, Cofilin1, Crmp1, ME2, and Odz4, involved in neuronal proliferation, differentiation, migration, and axon guidance. Each exhibits differential expression in wild type cortex. Odz4 is one of four members of a vertebrate gene family homologous to the Drosophila pair-rule patterning gene, Odd Oz (Odz), a transmembrane receptor. We show that Odz genes are expressed in complementary patterns in cortex, as well as in nuclei-specific patterns in thalamus that relates to their area-unique cortical expression. In addition, each of the genes analyzed shows different expression patterns in wild type cortex, Emx2, and Pax6 mutant cortex, consistent with potential roles in area patterning. These findings identify potential targets of EMX2 that might account for its function and the defects in Emx2-/- cortex, and suggest that the Odz family of transmembrane proteins influences cortical area patterning downstream to EMX2 and PAX6.

Animals↗
PubMed2002

DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death.

Death-associated protein kinase (DAPk) and DAPk-related protein kinase (DRP)-1 proteins are Ca+2/calmodulin-regulated Ser/Thr death kinases whose precise roles in programmed cell death are still mostly unknown. In this study, we dissected the subcellular events in which these kinases are involved during cell death. Expression of each of these DAPk subfamily members in their activated forms triggered two major cytoplasmic events: membrane blebbing, characteristic of several types of cell death, and extensive autophagy, which is typical of autophagic (type II) programmed cell death. These two different cellular outcomes were totally independent of caspase activity. It was also found that dominant negative mutants of DAPk or DRP-1 reduced membrane blebbing during the p55/tumor necrosis factor receptor 1-induced type I apoptosis but did not prevent nuclear fragmentation. In addition, expression of the dominant negative mutant of DRP-1 or of DAPk antisense mRNA reduced autophagy induced by antiestrogens, amino acid starvation, or administration of interferon-gamma. Thus, both endogenous DAPk and DRP-1 possess rate-limiting functions in these two distinct cytoplasmic events. Finally, immunogold staining showed that DRP-1 is localized inside the autophagic vesicles, suggesting a direct involvement of this kinase in the process of autophagy.

Antigens, CD↗
PubMed2000

Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium.

Severe psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder are brain diseases of unknown origin. No biological marker has been documented at the pathological, cellular, or molecular level, suggesting that a number of complex but subtle changes underlie these illnesses. We have used proteomic technology to survey postmortem tissue to identify changes linked to the various diseases. Proteomics uses two-dimensional gel electrophoresis and mass spectrometric sequencing of proteins to allow the comparison of subsets of expressed proteins among a large number of samples. This form of analysis was combined with a multivariate statistical model to study changes in protein levels in 89 frontal cortices obtained postmortem from individuals with schizophrenia, bipolar disorder, major depressive disorder, and non-psychiatric controls. We identified eight protein species that display disease-specific alterations in level in the frontal cortex. Six show decreases compared with the non-psychiatric controls for one or more diseases. Four of these are forms of glial fibrillary acidic protein (GFAP), one is dihydropyrimidinase-related protein 2, and the sixth is ubiquinone cytochrome c reductase core protein 1. Two spots, carbonic anhydrase 1 and fructose biphosphate aldolase C, show increase in one or more diseases compared to controls. Proteomic analysis may identify novel pathogenic mechanisms of human neuropsychiatric diseases.

Amino Acid Sequence↗
PubMed2005

Differential expression of CRMP1, CRMP2A, CRMP2B, and CRMP5 in axons or dendrites of distinct neurons in the mouse brain.

CRMP1, CRMP2, and CRMP5 have been identified as cytosolic proteins relaying semaphorin 3A signalling, one of the molecular cues conducting axon and dendrite growth and guidance. They are highly expressed during brain ontogenesis, but, because of their lower levels in the adult, their distribution in the mature brain is poorly documented. By using specific antibodies, we investigated the cellular distribution of these CRMPs in different adult brain structures and in neural cell cultures with a special focus on the splice variants CRMP2A and CRMP2B. In brain sections of adult mouse, CRMP1, CRMP2B, and CRMP5 were located predominantly in dendrites of specific neuronal populations, such as cortical pyramidal neurons, hippocampal CA1 pyramidal cells, or Purkinje cerebellar cells. On the contrary, CRMP2A was specifically associated with axons of the corpus callosum, bundles of the striatum, and mossy fibers of the hippocampus. In cultures of cortical neurons, CRMP1, CRMP2A, CRMP2B, and CRMP5 were equally distributed throughout cell bodies, axons, or dendrites of neurons, whereas CRMP2A and CRMP5 were completely absent from Purkinje cerebellar cells in 12-day-old animals. By comparison, oligodendrocytes exclusively express CRMP2B and CRMP5 in cell bodies and processes both in situ in the adult brain and in primary cultures. Overall, our results demonstrate specific subcellular localizations of CRMP1, CRMP2A, CRMP2B, and CRMP5 depending on cell types, neuronal compartment, and developmental stage. This study suggests that, beyond their signalling function in axon outgrowth and guidance, CRMPs also play a role in mature neurons both in axons and in dendrites.

Alternative Splicing↗
PubMed2006

Gene profiling and bioinformatic analysis of Schwann cell embryonic development and myelination.

To elucidate the molecular mechanisms involved in Schwann cell development, we profiled gene expression in the developing and injured rat sciatic nerve. The genes that showed significant changes in expression in developing and dedifferentiated nerve were validated with RT-PCR, in situ hybridisation, Western blot and immunofluorescence. A comprehensive approach to annotating micro-array probes and their associated transcripts was performed using Biopendium, a database of sequence and structural annotation. This approach significantly increased the number of genes for which a functional insight could be found. The analysis implicates agrin and two members of the collapsin response-mediated protein (CRMP) family in the switch from precursors to Schwann cells, and synuclein-1 and alphaB-crystallin in peripheral nerve myelination. We also identified a group of genes typically related to chondrogenesis and cartilage/bone development, including type II collagen, that were expressed in a manner similar to that of myelin-associated genes. The comprehensive function annotation also identified, among the genes regulated during nerve development or after nerve injury, proteins belonging to high-interest families, such as cytokines and kinases, and should therefore provide a uniquely valuable resource for future research.

Agrin↗
PubMed2001

Aberrant expression of dihydropyrimidinase related proteins-2,-3 and -4 in fetal Down syndrome brain.

Pathfinding of growing axons to reach their target during brain development is a subtle process needed to build up contacts between neurons. Abnormalities in brain development in Down Syndrome (DS) are described in a couple of morphological reports but the molecular mechanisms underlying abnormal wiring in fetal DS brain are not yet elucidated. We therefore performed a study using the proteomic approach to show differences in protein levels involved in the guidance of axons between control and DS brain in early prenatal life. Proteins obtained from autopsy of human fetal abortus were applied on 2-dimensional gel, identified and quantified. We quantified 5 members of the semaphorin/collapsin family, the dihydropyrimidinase related proteins 1-4 and the collapsin response mediator protein-5 (CRMP-5) in 8 DS and 7 control cortex samples. DRP-1 and CRMP-5 levels were comparable in the control and DS samples. Evaluation of DRP-2, DRP-3 and DRP-4 revealed significantly decreased levels of 2 of the 15 spots assigned to DRP-2 and increased levels of one spot assigned to DRP-3 and increased DRP-4 in DS brain. We conclude that as early as from the 19th week of gestation pathfinding cues of the outgrowing axons are impaired in DS. These findings may help to elucidate mechanisms leading to abnormalities in neural migration of DS brain.

Brain↗
PubMed2000

Differential expression of dihydropyrimidinase-related protein genes in developing and adult enteric nervous system.

Dihydropyrimidinase-related proteins (DRPs) are involved in axonal outgrowth and pathfinding. However, little is known about their significance in the enteric nervous system (ENS), the largest and most complex division of the peripheral nervous system. Using in situ hybridization (ISH) and northern blotting, we examined mRNA expression of DRP-1-4 transcripts in the developing and adult mouse digestive tract and in the adult human colon. ISH detected the mouse DRP-3 transcript in the developing ENS on embryonic day (E)12 and at the later stages as well as in the adult intestine. Mouse DRP-1 and -2 transcripts appeared at E14. DRP-2 transcript was also detected in the adult intestine although DRP-1 expression was lower in the adult. DRP-4 gene was not expressed in the ENS during development or adulthood whereas the signal was apparent in the developing and adult central nervous system (CNS). The DRP expression pattern in the human colon was similar to that of the mouse large intestine. Northern blot analysis showed that DRPs were differentially expressed in the mouse and human intestines, supporting the results of ISH. These data suggest that DRPs play a role not only in the CNS but also in the ENS.

Adult↗
PubMed2005

A human protein-protein interaction network: a resource for annotating the proteome.

Protein-protein interaction maps provide a valuable framework for a better understanding of the functional organization of the proteome. To detect interacting pairs of human proteins systematically, a protein matrix of 4456 baits and 5632 preys was screened by automated yeast two-hybrid (Y2H) interaction mating. We identified 3186 mostly novel interactions among 1705 proteins, resulting in a large, highly connected network. Independent pull-down and co-immunoprecipitation assays validated the overall quality of the Y2H interactions. Using topological and GO criteria, a scoring system was developed to define 911 high-confidence interactions among 401 proteins. Furthermore, the network was searched for interactions linking uncharacterized gene products and human disease proteins to regulatory cellular pathways. Two novel Axin-1 interactions were validated experimentally, characterizing ANP32A and CRMP1 as modulators of Wnt signaling. Systematic human protein interaction screens can lead to a more comprehensive understanding of protein function and cellular processes.

Axin Protein↗
PubMed2004

Involvement of collapsin response mediator proteins in the neurite extension induced by neurotrophins in dorsal root ganglion neurons.

The pattern of sensory neuron extensions and connections is established during embryonic development through complex and varied guidance cues that control motility of growth cones and neurite morphogenesis. Semaphorins and neurotrophins are molecules that act as such cues. Collapsin response mediator proteins (CRMPs) are thought to be part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse. In this report, we present evidence that CRMPs are also involved in the neurite extension controlled by neurotrophins. We found that specific antibodies and the dominant-negative mutant protein for CRMP2 both potentiated the neurite extension induced by NGF, while specific antibodies and the corresponding mutant protein for CRMP1 both abolished the neurite extension induced by NT3. Our data suggest that CRMP2 has a negative effect on neurite extension induced by NGF and CRMP1 participates in the neurite formation/extension induced by NT3. These results point to a function for CRMPs in the regulation of neurite outgrowth induced by neurotrophins in sensory neurons.

Amino Acid Sequence↗